Supplement to: Efficacy and Safety of Adjunctive Aripiprazole in Schizophrenia: Meta-Analysis of Randomized

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1 Supplement to: Efficacy and Safety of Adjunctive Aripiprazole in Schizophrenia: Meta-Analysis of Randomized Controlled Trials Wei Zheng, MD a, Ying-Jun Zheng, MD a, Xian-Bin Li, MD bc, Yi-Lang Tang, MD, PhD b,d, Chuan-Yue Wang, MD, PhD bc, Ying-Qiang Xiang, MD, PhD b, Jose de Leon, MD e,f,g a The Affiliated Brain Hospital of Guangzhou Medical University (Guangzhou Huiai Hospital), Guangzhou, China b Beijing Key Laboratory of Mental Disorders, Department of Psychiatry, Beijing Anding Hospital, Capital Medical University, Beijing , China c Center of Schizophrenia, Beijing Institute for Brain Disorders, Laboratory of Brain Disorders (Capital Medical University), Ministry of Science and Technology, Beijing , China d Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA e University of Kentucky, Mental Health Research Center at Eastern State Hospital, Lexington, KY, USA. f Psychiatry and Neurosciences Research Group (CTS-549), Institute of Neurosciences, University of Granada, Granada, Spain, g Biomedical Research Centre in Mental Health Net (CIBERSAM), Santiago Apostol Hospital, University of the Basque Country, Vitoria, Spain Address for reprints after publication: Wei Zheng, The Affiliated Brain Hospital of Guangzhou Medical University (Guangzhou Huiai Hospital), Guangzhou , China zhengwei0702@163.com, Fax: , Telephone:

2 TABLE OF CONTENTS SUPPLEMENTARY TABLE S1. Adjunctive Aripiprazole Randomized Controlled Trials in Schizophrenia: Description...3 SUPPLEMENTARY TABLE S2. Description of Sensitivity Analyses and Meta-Regressions...6 SUPPLEMENTARY TABLE S3. Adjunctive Aripiprazole Randomized Controlled Trials in Schizophrenia: GRADE Analyses:...7 SUPPLEMENTARY TABLE S4. Subgroup and Sensitivity Analysis of the Effect of Variables on the Total Psychopathology Scale Scores...9 SUPPLEMENTARY TABLE S5. Adjunctive Aripiprazole Randomized Controlled Trials in Schizophrenia: Secondary Outcomes...11 SUPPLEMENTARY TABLE S6. Subgroup Analysis and Sensitivity Analysis of the Effect of Variables on BMI...12 SUPPLEMENTARY TABLE S7. Adjunctive Aripiprazole Randomized Controlled Trials in Schizophrenia: RCTs Published in Chinese..14 SUPPLEMENTARY FIGURE S1. Legend SUPPLEMENTARY FIGURE S1. Computerized database search SUPPLEMENTARY FIGURE S2. Legend SUPPLEMENTARY FIGURE S2. Risk of bias of individual randomized controlled trials SUPPLEMENTARY FIGURE S3. Legend SUPPLEMENTARY FIGURE S3. Representation of risk of bias assessment in all randomized controlled trials grouped together SUPPLEMENTARY FIGURE S4. Legend SUPPLEMENTARY FIGURE S4. Funnel plot for total psychopathology SUPPLEMENTARY FIGURE S5. Legend SUPPLEMENTARY FIGURE S5. Funnel plot for weight SUPPLEMENTARY FIGURE S6. Legend SUPPLEMENTARY FIGURE S6. Funnel plot for BMI SUPPLEMENTARY FIGURE S7. Legend SUPPLEMENTARY FIGURE S7. Meta-analyses of discontinuations due to intolerability and inefficacy...40 SUPPLEMENTARY FIGURE S8. Legend SUPPLEMENTARY FIGURE S8. Meta-analyses of adverse drug reactions SUPPLEMENTARY FIGURE S9. Legend SUPPLEMENTARY FIGURE S9. Meta-analyses of adverse drug reactions (continuation 1) SUPPLEMENTARY FIGURE S10. Legend SUPPLEMENTARY FIGURE S10. Meta-analyses of adverse drug reactions (continuation 2) SUPPLEMENTARY FIGURE S11. Legend SUPPLEMENTARY FIGURE S11. Meta-analyses of adverse drug reactions (continuation 3)

3 SUPPLEMENTARY TABLE S1. Adjunctive Aripiprazole Randomized Controlled Trials in Schizophrenia: Description Design Schizophrenia patients Interventions h Duration/ Age/ Male Illness Jadad i Author Country N a weeks Blinding Co-treatment b Dose c Setting d years % e Criteria f Phase g Duration AP (dose mg/day) N score ARIPRAZOLE ADDED TO CLOZAPINE Patients N=1690 (RCT N=21) Chang 10 Korea 62 8 Double Augmentation Standard Both DSM-IV Refractory NR 1.CLO (304) N= CLO (291) + ARI (16) N=30 Chi 11 China Open-label Simultaneous Reduced Inpatients 36.7 NR CCMD-3 Refractory CLO (332) N=20 2. CLO (101) + ARI (17) N=20 2 Deng 12 China Open-label Simultaneous Reduced NR NR Chronic CLO (NR) N= CLO (NR) +ARI (NR) N=34 Ding 13 China 66 8 Open-label Simultaneous Reduced Outpatients CCMD-3 Refractory CLO (NR) N= CLO (NR) + ARI (NR) N=33 Fan 14 USA 38 j 8 Double Augmentation Standard Inpatients DSM-IV Chronic NR 1. CLO (400) N= CLO (397) + ARI (15) N=20 Fleischhacker 15 Europe Double Augmentation Standard Outpatients DSM-IV Refractory CLO (363) N=108 4 and South 2. CLO (384) + ARI (11) N=99 Africa Guan 16 China Open-label Augmentation Reduced Inpatients NR 50 ICD-10 Refractory NR 1. CLO (NR) N= CLO(NR) +ARI (NR) N=30 Li 17 China Open-label Simultaneous Reduced Inpatients CCMD-3 Refractory CLO (NR) N= CLO (NR) + ARI (NR) N=32 Liang 18 China Open-label Simultaneous Reduced Both CCMD-3 Chronic CLO (NR) N= CLO (NR) + ARI (NR) N=24 Luo 19 China Open-label Simultaneous Reduced Inpatients ICD-10 Chronic CLO (NR) N=43 2 Ma CLO (100) + ARI (NR) N=43 China Open-label Augmentation Reduced NR ICD-10 Refractory CLO (NR) N= CLO (118) + ARI (20) N=48 Muscatello 21 Italy Double Augmentation Standard Outpatients DSM-IV Chronic NR 1. CLO (314) N= CLO (310) + ARI (11) N=20 Ren 22 China 60 8 Open-label Simultaneous Reduced Inpatients CCMD-3 Refractory CLO (NR) N= CLO (NR) + ARI (NR) N=30 Sun 23 China 64 8 Open-label Simultaneous Standard Inpatients CCMD-3 Refractory CLO (250) N= CLO (250) + ARI (12) N=32 Sun 24 China Open-label Augmentation Reduced Inpatients CCMD-3 Chronic CLO (368) N= CLO (168) + ARI (21) N=32 Wang 25 China 92 8 Open-label Simultaneous Reduced NR CCMD-3 Chronic CLO (NR) N= CLO (NR) + ARI (30) N=46 Wang 26 China Open-label Simultaneous Reduced Inpatients CCMD-3 Chronic CLO (227) N= CLO (182) + ARI (12) N=45 Xu 27 China 97 8 Open-label Simultaneous Reduced Inpatients CCMD-3 Chronic NR 1. CLO (350) N= CLO (155) + ARI (26) N=49 Xu 28 China 92 8 Open label Simultaneous Reduced Inpatients NR Chronic CLO (NR) N= CLO (NR) + ARI (30) N=46 Yin 29 China Open-label Simultaneous Reduced Inpatients CCMD-3 Refractory ARI (25) N= CLO (375) N=30 3. CLO 106) + ARI (15) N=30 Zhang 30 China Open-label Augmentation Standard Inpatients CCMD-3 Refractory >10 1. CLO (NR) N= CLO (NR) + ARI (10) N=84 3

4 ARIPRAZOLE ADDED TO ANOTHER ANTIPSYCHOTIC Patients N=2747 (RCT N=34) Chen 31 China 86 8 Open-label Simultaneous Standard Inpatients NR 0 CCMD-3 Acute NR 1. OLA (NR) N= OLA (NR) + ARI (10) N=40 Chen 32 China Open-label Simultaneous Reduced Outpatients ICD-10 Chronic RIS (NR) N= RIS (NR) + ARI (16) N=50 Chen 33 China Double Augmentation Standard NR ICD-10 Chronic RIS (5) N= RIS (5) + ARI (20) N=59 Henderson 34 USA 14 4 Double Augmentation Standard Outpatients DSM-IV Chronic NR 1. OLA (22) N= OLA (22) + ARI (15) N=7 Jin 35 China 80 6 Double Augmentation Standard Both CCMD-3 Chronic CPZ (238) N= CPZ (258) + ARI (5) N=40 Kane 36 USA 323 k 16 Double Simultaneous Standard Outpatients DSM-IV Chronic NR 1. QUE (516) + RIS (5) N= QUE (513) + RIS (5) + ARI (10) N=168 Lai 37 Lee 38 China 40 8 Open-label Simultaneous Reduced Inpatients NR NR ICD-10 Acute NR 1. OLA (25) N= OLA (12) +ARI (16) N=20 Korea Double Augmentation Standard NR DSM-IV Chronic RIS (3) N= RIS (3) + ARI (10) N=17 Li 39 China Open-label Simultaneous Standard NR ICD-10 Chronic RIS (NR) N= RIS (NR) + ARI (NR) N=55 Li 40 China 80 8 Open-label Simultaneous Standard Inpatients CCMD-3 Acute SUL (NR) N= SUL (NR) + ARI (NR) N=40 Li 41 China 70 6 Open-label Simultaneous Standard Both ICD-10 Chronic OLA (17) N= OLA (17) + ARI (10) N=35 Li 42 China 60 4 Open-label Augmentation Standard Inpatients CCMD-3 Chronic OLA (4) N= OLA (4) + ARI (20) N=32 Liang 43 China 41 4 Double Simultaneous Reduced Both DSM-IV Chronic PAL (10) N= PAL (6) + ARI (10) N=20 Liu 44 China 70 6 Open-label Simultaneous Standard Both ICD-10 Chronic RIS (5) N= RIS (5) + ARI (10) N=35 Ou 45 China 70 8 Open-label Augmentation Standard Inpatients CCMD-3 Chronic OLA (18) N=35 3 Pan 46 China 58 6 Rater Augmentation Standard NR NR 0 CCMD-3 Chronic APs (NR) N=29 3 masked 2. APs (NR) + ARI (10) N=29 2. OLA (18) + ARI (10) N=35 Pan 47 China 80 6 Open-label Simultaneous Standard Inpatients CCMD-3 Acute OLA (17) N= OLA (40) + ARI (10) N=40 Ren 48 China 72 8 Rater Simultaneous Standard Outpatients NR NR ICD-10 Acute NR 1. SUL (NR) N=36 3 masked 2. SUL (NR) + ARI (NR) N=36 Shim 49 Korea 54 8 Double Augmentation Standard NR DSM-IV Chronic HAL (25) N=28 4 Shu HAL (21) + ARI (NR) N=26 China Open-label Simultaneous Standard Outpatients CCMD-3 Acute 3 1. RIS (4) N= RIS (4) + ARI (7) N=30 Sun 51 China Open-label Augmentation Standard Inpatients ICD-10 Chronic NR 1. OLA (15) N= OLA (15) + ARI (10) N=28 Sun 52 China 34 6 Open-label Augmentation Standard Inpatients CCMD-3 Chronic NR 1. RIS (4) N= RIS (3) + ARI (5) N=17 Wang 53 China 70 8 Open-label Simultaneous Standard Inpatients CCMD-3 Chronic RIS (5) N= RIS (5) + ARI (5) N=35 Wang 54 China Open-label Simultaneous Reduced Inpatients ICD-10 Chronic AMI (NR) N= AMI (NR) + ARI (NR) N=40 Xiong 55 China 68 8 Open-label Simultaneous Standard NR CCMD-3 Chronic RIS (4) N=34 2 4

5 Xu 56 China 68 6 Open-label Simultaneous Standard Both ICD-10 Chronic RIS (4) +ARI (10) N=34 1. QUE (624) N=32 2 Xue 57 China 68 6 Rater Augmentation Standard Inpatients 42.4 NR CCMD-3 Chronic NR 2. QUE (604) + ARI (10) N=31 1. RIS (5) N=34 3 Yang 58 China masked Double Same time Standard NR CCMD-3 Acute RIS (5) + ARI (5) N=34 1. RIS (5) N= ARI (5) N=60 Yang 59 China Open-label Same time Reduced Both CCMD-3 Chronic RIS (5) + ARI (10) N=60 1. RIS (NR) N= RIS (NR) + ARI (NR) N=105 Yasui- Furukori 60 Japan Double Augmentation Standard Outpatients DSM-IV Chronic RIS (5) + OLA (13) N=18 2. RIS (6) + OLA (12) + ARI (15) N=18 Zhao 61 China Open-label Augmentation Standard Both NR 0 CCMD-3 Chronic NR 1. RIS (NR) N= RIS(NR)+ARI(10)N=28 Zhou 62 China Rater Augmentation Standard Both ICD-10 Chronic RIS (4) N=30 3 masked 2. RIS (4) + ARI (10) N=30 Zhou 63 China Open-label Augmentation Standard Both NR 0 CCMD-3 Chronic NR 1. RIS (NR) N=50 3 Zhuo 64 China Double Augmentation Standard NR NR Chronic RIS (NR) + ARI (5) N=50 1. APs (NR) N= APs (NR) + ARI (23) N=30 55 RCTs 4457 l 10.1 l 34.9 l 44.2 l 7.0 l Chinese ± Double- 33Augmentation 35 Standard 10 NR ±6.0 ± NR 7Acute ± CLO ±0.8 blind 9 Non-Chinese 4 Rater 22 Same time 20 Reduced 9 Outpatients 9 CCMD-3 37 Chronic 14 RIS masked 37 Open- 26 Inpatients 14 ICD Refractory 9 OLA m label 10 Both 10 DSM-IV NR, not reported; RCT, randomized clinical trial. a This number reflects the total sample size recruited, including patients on aripiprazole and placebo. b Co-treatment with aripiprazole was started simultaneously with the other antipsychotic or added as an augmentation strategy. c The dose of the other antipsychotic was the standard dose or was reduced when aripiprazole was added. d The setting was classified as inpatient, outpatient or both. e Percentage of males who completed the study. f Diagnostic criteria used to diagnose schizophrenia. CCMD-3, China's mental disorder classification and diagnosis, standard 3 rd edition; DSM-IV, Diagnostic and Statistical Manual of Mental Disorders, 4 th edition; ICD-10, International Classification of Diseases, 10 th edition. g Phase was classified as acute, chronic or refractory. All acute phase studies were completed in first-episode patients. Refractory-phase studies included chronic patients who also were considered refractory to treatment. h In 53 RCTs the two comparison interventions are listed as 1 and 2. In two trials there were 3 interventions listed as 1, 2 and 3. In each intervention the mean daily dose prescribed was included in parentheses when it was described, followed by the number of patients, N, taking this treatment. AP, antipsychotic; AMI, amisulpiride; ARI, aripiprazole; CLO, clozapine; CPZ, chlorpromazine; HAL, haloperidol; OLA, olanzapine; PAL, paliperidone; QUE, quetiapine; RIS, risperidone; SUL, sulpiride. i The Jadad scale focused on five criteria: randomization, double blinding, description withdrawals and dropouts, generation of random numbers, and allocation concealment for assessing the quality of RCTs. One point was given for each area addressed in the study. The total Jadad score ranged from a minimum of 0 to a maximum of 5 points. RCTs were classified as high quality if their Jadad score was 4 and low quality if their Jadad score was <4. j Only 30 of 38 patients completed the study, including 20 patients with schizophrenia and 10 with schizoaffective disorder. k The 323 patients were diagnosed with schizophrenia (n=252) or schizoaffective disorder (n=71). l Mean ± standard deviation calculated used available data. In some columns there were studies with NR data. m Other less frequent trials included 4 APs, 2 SUL, 1 CPZ, 1 AMI, 1 HAL, 1 QUE, and 1 PAL. 5

6 SUPPLEMENTARY TABLE S2. Description of Sensitivity Analyses and Meta-Regressions Sensitivity analyses We conducted 14 subgroup analyses in order to identify potential moderators or mediators of the effect on total psychopathology and BMI. These subgroup analyses included: (1) Chinese vs. non-chinese studies (2) Studies describing vs. those not describing randomization details (3) Double blind/rater-masked vs. non-blinded studies (4) Illness phase classified into 3 groups: acute (all were first-episode trials), chronic, or refractory (5) Standard vs. reduced antipsychotic doses in the co-treatment arm (6) Simultaneous augmentation vs. delayed augmentation after nonresponse (7) Treatment duration <12 weeks vs. 12 weeks (8) Added to clozapine vs. another antipsychotic (9) Aripiprazole co-treatment with first-generation antipsychotic compared with first-generation antipsychotic vs. aripiprazole co-treatment with second-generation antipsychotic (10) Male predominance ( 60%), female predominance ( 60%), and no sex predominance (11) Jadad score (high quality) vs. Jadad score < 4 (low quality) (12) Inpatients, outpatients, and in-outpatients (13) Last observation carried forward vs. observed cases (14) Placebo vs. comparison antipsychotic (15) Studies with blinding and 12 weeks vs. other studies Meta-regression analyses Meta-regression analyses including available data were conducted in order to examine the potentially moderating and mediating effect on outcomes of: (1) RCT duration (2) Mean age of study participants (3) Percentage of males (4) Illness duration (5) Chinese vs. non-chinese (6) Blinded vs. non-blinded (7) Illness phase Outcomes included: (1) PANSS/BPRS total score change/endpoint difference (2) Body weight (3) BMI change difference BMI, body mass index; BPRS, Brief Psychiatric Rating Scale; PANSS, Positive and Negative Symptoms Scale; RCT, randomized clinical trial. 6

7 SUPPLEMENTARY TABLE S3. Adjunctive Aripiprazole Randomized Controlled Trials in Schizophrenia: GRADE Analyses Primary/secondary outcomes a N b (studies) Risk of bias c Inconsistency d Indirectness Imprecision Publication bias Large effect e Is it plausible that confounding Dose response gradient Overall quality of evidence f factors would change the effect? PANSS/BPRS total score 3351 (43) Serious Serious No No Undetected No No No +/+/-/-/; Low PANSS Positive Symptom 2223 (29) Serious Serious No No Undetected No No No +/+/-/-/; Low Sub-Score PANSS Negative Symptom 2294 (30) Serious Serious No No Undetected No No No +/+/-/-/; Low Sub-Score PANSS General Symptom 1138 (13) Serious Serious No No Undetected No No No +/+/-/-/; Low Sub-Score Body weight (kg) 505 (9) Serious No No No Undetected No No No +/+/+/; Moderate Body mass index 809 (14) Serious No No No Undetected No No No +/+/+/; Moderate Waist circumference (cm) 218 (5) Serious No No No Undetected No No No +/+/+/; Moderate Serum triglycerides (mg/dl) 631 (9) Serious Serious No No Undetected No No No +/+/-/-/; Low Serum total cholesterol 692 (10) Serious Serious No No Undetected No No No +/+/-/-/; Low (mg/dl) HDL cholesterol (mg/dl) 544 (8) Serious Serious No No Undetected No No No +/+/-/-/; Low LDL cholesterol (mg/dl) 540 (8) Serious Serious No No Undetected No No No +/+/-/-/; Low Fasting glucose (mg/dl) 710 (10) Serious No No No Undetected No No No +/+/+/; Moderate Prolactin (ng/ml) 1038 (15) Serious Serious No No Undetected No No No +/+/-/-/; Low TESS total score 559 (9) Serious Serious No No Undetected No No No +/+/-/-/; Low Anxiety 348 (3) No Serious No No Undetected No No No +/+/+/; Moderate Weight gain 1079 (13) Serious No No No Undetected Large No No +/+/+/+/; High Drowsiness 983 (10) Serious Serious No No Undetected No No No +/+/-/-/; Low 7

8 Constipation 920 (13) Serious No No No Undetected Large No No +/+/+/+/; High Extrapyramidal symptoms 506 (5) Serious No No No Undetected No No No +/+/+/; Moderate Drooling/hypersalivation 679 (10) Serious No No No Undetected No No No +/+/+/; Moderate Tachycardia 807 (11) Serious No No No Undetected No No No +/+/+/; Moderate Electrocardiographic 557 (7) Serious No No No Undetected Large No No +/+/+/+/; High abnormality All cause-discontinuation 1953 (22) Serious No No No Undetected No No No +/+/+/; Moderate Discontinuation due to 729 (6) No No No No Undetected No No No +/+/+/+/; High intolerability Discontinuation due to 730 (5) No No No No Undetected No No No +/+/+/+/; High inefficacy a This row describes all studies reporting that primary (in bold) or secondary (in bold and italic) measure. Subgroups of studies from the same measure may be described in succeeding rows. HDL-C, high density lipoprotein cholesterol; LDL-C, low density lipoprotein cholesterol; TESS, treatment emergent symptom scale; EKG = electrocardiogram. b N=total number of individuals after adding all studies providing that outcome. The number of studies is described in parentheses. c All studies reported as having a serious bias used a single-blind method and only mentioned random allocation without describing the method. d All studies reported as having a serious inconsistency had I 2 > 50%. e Studies with large effects (or even more with very large) provided increased quality of evidence. Large effects= 2<RR<0.5. Very large effects= 5<RR<0.2. RR, risk ratios. f GRADE Working Group grades of evidence: High quality=further research is very unlikely to change our confidence in the estimate of effect. Moderate quality=further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality=further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality=we are very uncertain about the estimate. GRADE, grading of recommendations, assessment, development, and evaluation. 8

9 SUPPLEMENTARY TABLE S4. Subgroup and Sensitivity Analysis of the Effect of Variables on the Total Psychopathology Scale Scores a N Variable Patients (RCTs) SMD (95% CI) I 2 (%) p c 1. Origin: Chinese 2931 (37) (-0.75, -0.30) 88 < Non-Chinese 420 (6) (-0.41, 0.14) Description of randomization details: Yes 1182 (14) (-0.91, -0.10) No 2169 (29) (-0.70, -0.23) 86 < Blinded studies: Yes b 916 (12) (-0.50, 0.13) No b 2435 (31) (-0.83, -0.34) 88 < Phase: Acute 455 (6) (-0.93, -0.10) $ Chronic 2154 (27) (-0.60, -0.08) $ Refractory 742 (10) (-1.22, -0.46) $ 83 < Dose: Standard 1996 (26) (-0.57, -0.10) Reduced 1355 (17) (-1.05, -0.35) Co-treatment: Simultaneous 2207 (29) (-0.79, -0.28) 88 < Augmentation 1144 (14) (-0.67, -0.04) Trial duration: < 12 weeks 2025 (26) (-0.73, -0.17) weeks 1326 (17) (-0.80, -0.22) Added to clozapine: Yes 1453 (18) (-0.88, -0.28) No 1898 (25) (-0.68, -0.12) ARI + FGA vs. FGA 374 (4) (-1.00, -0.05) ARI + SGA vs. SGA 2977 (39) (-0.69, -0.25) 88 < Predominance: Males ( 60%) 732 (8) (-1.19, -0.20) Females ( 60%) 617 (10) (-0.20, 0.19) None 1762 (21) (-0.99, -0.37) 90 < Jadad score: 4 (high quality) 639 (8) (-0.39, 0.03) < 4 (low quality) 2712 (35) (-0.77, -0.29) 89 < Setting: Inpatients 1454 (20) (-0.66, -0.20) Outpatients 570 (7) (-0.92, -0.02) Both 723 (9) (-0.79, 0.33) Last observation carried forward 2890 (36) (-0.75, -0.28) 89 < Observed cases 461 (7) (-0.60, -0.00) Control: Placebo b 916 (12) (-0.50, 0.13) Other comparison: an antipsychotic b 2435 (31) (-0.83, -0.34) 88 < Studies with blinding and 12 weeks 307 (4) (-0.64, 0.29)

10 Other studies 3044 (39) (-0.72, -0.29) 88 < ARI, aripiprazole; CI, 95% confidence interval; FGA, first-generation antipsychotics; RCT, randomized clinical trials; SGA, second-generation antipsychotics; SMD, standardized mean difference. a Outcome is measured by change or endpoint of the total scores on the PANSS, Positive and Negative Symptoms Scale, or the BPRS, Brief Psychiatric Rating Scale. b The same 12 RCTs were blinded and used placebo. Therefore, the subgroup analysis variables Number 3 blinded yes vs. no and Number 14 control placebo vs. comparison antipsychotic provided the same results. c p-values <0.05 are bolded. 10

11 SUPPLEMENTARY TABLE S5. Adjunctive Aripiprazole for Schizophrenia-Spectrum Disorders: Secondary Outcomes N a SMD or I 2 Secondary outcomes Patients (RCTs) WMD b (CI) (%) p c PANSS/BPRS Positive symptom sub-score 2223 (29) (-0.26, 0.25) PANSS/BPRS Negative symptom sub-score 2294 (30) (-0.91, -0.31) 91 < PANSS General symptom sub-score 1138 (13) (-7.23,-0.81) Waist circumference (cm) 174 (3) (-6.89, 1.48) Prolactin (ng/ml) 1038 (15) (-62.64, ) 100 < Fasting glucose (mg/dl) 710 (10) (-6.48,-1.46) Serum triglycerides (mg/dl) 631 (9) (-35.50, -4.87) Serum total cholesterol (mg/dl) 692 (10) (-34.83, 15.27) HDL cholesterol (mg/dl) 544 (8) (-4.65, 4.23) LDL cholesterol (mg/dl) 540 (8) (-9.39, -2.01) TESS total score 559 (9) (-1.26, -0.02) BPRS, Brief Psychiatric Rating Scale; CI, 95% confidence interval; HDL, High Density Lipoprotein; LDL, Low Density Lipoprotein; PANSS, Positive and Negative Symptoms Scale; RCT, randomized clinical trial; SMD, standardized mean difference; TESS: Treatment Emergent Symptom Scale; WMD, weighted mean difference. a Patients refers to the total number of individuals included in the statistical analysis. In parentheses, the number of RCTs from which these patients come. b WMDs were calculated in these analyses. c P-values <0.05 are bolded. 11

12 SUPPLEMENTARY TABLE S6. Subgroup Analysis and Sensitivity Analysis of the Effect of Variables on BMI N Variable 1. Origin: Chinese Patients (RCTs) 704 (11) WMD (95% CI) (-2.17, -1.36) I 2 (%) 43 p a < Non-Chinese 105 (3) (-5.86, 2.19) Description of randomization details: Yes 369 (6) (-2.38, -1.12) 55 < No 440 (8) (-2.62, -1.13) 55 < Blinded studies: Yes b 283 (6) (-2.82, -0.83) No b 526 (8) (-2.15, -1.18) 32 < Phase: Acute 80 (1) (-2.23, -0.57) N/A Chronic 628 (11) (-2.41, -1.36) 54 < Refractory 101 (2) (-4.15, 1.90) Dose: Standard 628 (12) (-2.48, -1.41) 53 < Reduced 181 (2) (-1.65, -0.68) 0 < Co-treatment: Simultaneous 324 (4) (-1.73, -0.87) 3 < Augmentation 485 (10) (-2.61, -1.35) 57 < Trial duration: < 12 weeks 547 (9) (-2.15, -0.94) 53 < weeks 262 (5) (-2.90, -1.41) 50 < Added to clozapine: Yes 312 (5) (-2.88, -0.30) No 497 (9) (-2.29, -1.42) 29 < ARI + FGA vs. FGA 63 (1) (-4.90, -0.90) N/A ARI + SGA vs. SGA 746 (13) (-2.21, -1.26) 55 < Predominance: Males ( 60%) 225 (5) (-3.30, -0.34) Females ( 60%) 283 (5) (-2.97, -1.92) 0 < None 301 (4) (-1.57, -0.85) 0 < Jadad score: 4 (high quality) 121 (2) (-3.95, 1.75) < 4 (low quality) 688 (12) (-2.24, -1.31) 45 < Setting c : Inpatients 354 (6) (-2.79, -1.13) 54 < Outpatients 14 (1) (-5.52, -4.12) N/A 0.78 Both 234 (4) (-2.80, -0.25) Last observation carried forward 554 (9) (-2.05, -1.05) 52 < Observed cases 255 (5) (-3.74, -1.49) 55 < Control: Placebo b 283 (6) (-2.82, -0.83) Other comparison antipsychotic b 526 (8) (-2.15, -1.18) 32 < Studies with blinding and 12 weeks 120 (2) (-3.01, -0.54)

13 Other studies 689 (12) (-2.35, -1.25) 53 < ARI, aripiprazole; BMI, body mass index; CI, 95% confidence interval; FGA, first-generation antipsychotics; N/A, not applicable. RCTs, randomized clinical trials; SGA, second-generation antipsychotics; WMD, weighted mean difference. a P-values <0.05 are bolded. b The same 6 RCTs were blinded and used placebo. Therefore, the subgroup analysis variables Number 3 blinded yes vs. no and Number 14 control placebo vs. comparison antipsychotic provided the same results. c Only 11 RCTs reported the setting. 13

14 Supplementary Table 7. Adjunctive Aripiprazole Randomized Controlled Trials in Schizophrenia: RCTs Published in Chinese a First Author: Chi 11 Illness Stage: Refractory patients Trial Design: A 12-week randomized, open-label trial Sample: All 40 inpatients meeting inclusion criteria: 1) both sexes, 2) PANSS 60, 3) the CCMD-3 diagnostic criteria for refractory schizophrenia, and 4) failure of treatment with 2 different classes for 4 weeks ( 600 mg/day CPZE). Exclusion criteria were relevant medical conditions, drug or alcohol abuse. Treatment: CLO (101 mg/day) + ARI (17 mg/day) (N=20) Comparisons: CLO (332 mg/day) (N=20) Outcomes: PANSS, TESS and discontinuation rate First Author: Deng 12 Trial Design: A 12-week randomized, open-label trial Sample: All 68 patients meeting inclusion criteria: 1) failure of treatment with APs and 2) failure to tolerate AP-induced ADRs. Exclusion criteria were relevant medical conditions, drug or alcohol abuse, pregnancy or breastfeeding in females. Treatment: CLO (NR) +ARI (NR) (N=34) Comparison: CLO (NR) (N=34) Outcomes: PANSS, TESS and discontinuation rate First Author: Ding 13 Illness Stage: Refractory patients Trial Design: An 8-week randomized, open-label trial Sample: All 66 outpatients meeting inclusion criteria: 1) refractory schizophrenia, 2) both sexes and 3) PANSS 60. Exclusion criteria were relevant medical conditions, drug or alcohol abuse. Treatment: CLO (NR) + ARI (NR) (N=33) Comparison: CLO (NR) (N=33) Outcomes: PANSS, TESS and discontinuation rate First Author: Guan 16 Illness Stage: Refractory patients Trial Design: A 16-week randomized, open-label trial Sample: All 60 inpatients meeting inclusion criteria: 1) ICD-10 diagnostic criteria for schizophrenia, 2) both sexes, 3) PANSS 80s and 4) failure of treatment with 2 different AP classes for 8 weeks and CLO-resistant (>500 mg/day). Exclusion criteria were relevant medical 14

15 conditions, drug or alcohol abuse. Treatment: CLO (NR) +ARI (NR) (N=30) Comparison: CLO (NR) (N=30) Outcomes: PANSS and TESS First Author: Li 17 Illness Stage: Refractory patients Trial Design: A 12-week randomized, open-label trial Sample: 64 female inpatients meeting inclusion criteria: 1) failure of treatment with 3 different AP classes for 12 weeks. Exclusion criteria were relevant medical conditions or drug or alcohol abuse. Treatment: CLO (NR) + ARI (NR) (N=32) Comparison: CLO (NR) (N=32) Outcomes: PANSS, TESS, and discontinuation rate First Author: Liang 18 Trial Design: A 12-week randomized, open-label trial Sample: All 48 in/outpatients with schizophrenia meeting inclusion criteria: 1) CCMD-3 diagnostic criteria, 2) both sexes and 3) PANSS 60. Exclusion criteria were relevant medical conditions, drug or alcohol abuse, pregnancy or breastfeeding in females. Treatment: CLO (NR) + ARI (NR) (N=24) Comparison: CLO (NR) (N=24) Outcomes: PANSS, WCST, CPT, TESS, and discontinuation rate First Author: Luo 19 Trial Design: A 12-week randomized, open-label trial Sample: All 86 inpatients with schizophrenia meeting inclusion criteria: 1) ICD-10 diagnostic criteria, 2) both sexes and 3) PANSS 70. Exclusion criteria were relevant medical conditions, drug or alcohol abuse, pregnancy or breastfeeding in females. Treatment: CLO (100 mg/day) + ARI (NR) (N=43) Comparison: CLO (NR) (N=43) Outcomes: PANSS, TESS, and discontinuation rate First Author: Ma 20 Illness Stage: Refractory patients Trial Design: A 12-week randomized, open-label trial 15

16 Sample: All 96 patients with schizophrenia meeting inclusion criteria: 1) CCMD-3 diagnostic criteria, 2) both sexes and 3) failure of treatment with 4 APs from 3 different classes for 6 weeks and 5) CLO-resistant (>500 mg/day). Exclusion criteria were relevant medical conditions, drug or alcohol abuse. Treatment: CLO (118 mg/day) + ARI (20 mg/day) (N=48) Comparisons: CLO (NR) monotherapy (N=48) Outcomes: BPRS, TESS, and discontinuation rate First Author: Ren 22 Illness Stage: Refractory patients Trial Design: An 8-week randomized, open-label trial Sample: All 60 inpatients with schizophrenia meeting inclusion criteria: 1) CCMD-3 diagnostic criteria, 2) both sexes, 3) PANSS >60 and 4) failure of treatment with 3 APs from 2 different classes for 6 weeks. Exclusion criteria were relevant medical conditions, drug or alcohol abuse, pregnancy or breastfeeding in females, or other mental diseases. Treatment: CLO (NR) + ARI (NR)( N=30) Comparisons: CLO (NR) (N=30) Outcomes: PANSS, TESS and discontinuation rate First Author: Sun 23 Illness Stage: Refractory patients Trial Design: An 8-week randomized, open-label trial Sample: All 64 male inpatients meeting inclusion criteria: 1) the CCMD-3 diagnostic criteria for refractory schizophrenia, 2) PANSS 60 and 3) failure of treatment with at 3 different AP classes for 6 weeks with CPZE ( 600 mg/day). Exclusion criteria were relevant medical conditions, drug or alcohol abuse. Treatment: CLO (250 mg/day) + ARI (12 mg/day) ( N=32) Comparison: CLO (250 mg/day) (N=32) Outcomes: PANSS, TESS and discontinuation rate First Author: Sun 24 Trial Design: A 12-week randomized, open-label trial Sample: All 62 inpatients with schizophrenia meeting inclusion criteria: 1) CCMD-3 diagnostic criteria, 2) both sexes and 3) PANSS 70. Exclusion criteria were relevant medical conditions, drug or alcohol abuse. Treatment: CLO (168 mg/day) + ARI (21 mg/day) (N=32) Comparison: CLO (368 mg/day) (N=30) 16

17 Outcomes: PANSS, TESS and discontinuation rate First Author: Wang 25 Trial Design: An 8-week randomized, open-label trial Sample: All 92 patients with schizophrenia meeting inclusion criteria: 1) the CCMD-3 diagnostic criteria, 2) both sexes and 3) WBC >6,500/mm. 3 Exclusion criteria were relevant medical conditions, drug or alcohol abuse. Treatment: CLO (NR) + ARI (30 mg/day) (N=46) Comparison: CLO (NR) (N=46) Outcomes: PANSS, TESS and discontinuation rate First Author: Wang 26 Trial Design: A 12-week randomized, open-label trial Sample: All 90 inpatients meeting inclusion criteria: 1) the CCMD-3 diagnostic criteria for schizophrenia, 2) both sexes and 3) PANSS 60. Exclusion criteria were relevant medical conditions, drug or alcohol abuse, pregnancy or breastfeeding in females. Treatment: CLO (NR) + ARI (30 mg/day) (N=45) Comparisons: CLO (NR) (N=45) Outcomes: PANSS and TESS and discontinuation rate First Author: Xu 27 Trial Design: An 8-week randomized, open-label trial Sample: All 97 inpatients with schizophrenia meeting inclusion criteria: 1) the CCMD-3 diagnostic criteria, 2) both sexes and 3) PANSS >60. Exclusion criteria were relevant medical conditions, drug or alcohol abuse, pregnancy or breastfeeding in females. Treatment: CLO (155 mg/day) + ARI (26 mg/day) ( N=49) Comparisons: CLO (350 mg/day) (N=48) Outcomes: PANSS and TESS First Author: Xu 28 Trial Design: An 8-week randomized, open-label trial Sample: All 92 inpatients with schizophrenia meeting inclusion criteria: 1) the CCMD-3 diagnostic criteria and 2) both sexes. Exclusion criteria were relevant medical conditions, drug or alcohol abuse. Treatment: CLO (NR) + ARI (30 mg/day) (N=46) 17

18 Comparison: CLO (NR) (N=46) Outcomes: PANSS, TC, TGs, HDL-C, LDL-C, BMI, FG and discontinuation rate First Author: Yin 29 Illness Stage: Refractory patients Trial Design: A 12-week randomized, open-label trial Sample: All 90 inpatients with schizophrenia meeting inclusion criteria: 1) the CCMD-3 diagnostic criteria, 2) both sexes, 3) PANSS 60 and 4) failure of treatment with APs with 3 different classes for 12 weeks ( mg/day of CPZE). Exclusion criteria were relevant medical conditions, drug or alcohol abuse, pregnancy or breastfeeding in females. Treatment: CLO (106 mg/day) + ARI (15 mg/day) (N=30) Comparison:ARI (25 mg/day) (N=30), CLO (375 mg/day) (N=30) Outcomes: PANSS, GAF, TESS and discontinuation rate First Author: Zhang 30 Illness Stage: Refractory patients Trial Design: A 24-week randomized, open-label trial Sample: All 168 inpatients with schizophrenia meeting inclusion criteria: 1) the CCMD-3 diagnostic criteria, 2) both sexes, 3) ages years and 4) failure of treatment with 2 APs for 6 to 8 weeks. Exclusion criteria were relevant medical conditions, pregnancy or breastfeeding in females. Treatment: CLO (NR) + ARI (10 mg/day) (N=84) Comparison: CLO (NR) (N=84) Outcomes: BRPS, TESS, and discontinuation rate First Author: Chen 31 Illness Stage: Acute patients Trial Design: An 8-week randomized, open-label trial Sample: 86 female inpatients with schizophrenia meeting inclusion criteria: 1) the CCMD-3 diagnostic criteria and 2) ages from 18 to 55 years. Exclusion criteria were treatment with any AP before the trial. Treatment: OLA (NR) + ARI (10 mg/day) ( N=40) Comparisons: OLA (NR) (N=46) Outcomes: PANSS, BMI and PRL First Author: Chen 32 Trial Design: An 8-week randomized, open-label trial 18

19 Sample: All 100 outpatients with schizophrenia meeting inclusion criteria: 1) the ICD-10 diagnostic criteria and 2) both sexes. Treatment: RIS (NR) + ARI (16 mg/day) ( N=50) Comparison: RIS (NR) (N=50) Outcomes: PANSS, TESS and discontinuation rate First Author: Chen 33 Trial Design: An 8-week randomized, double-blind, placebo-controlled trial Sample: All 116 female patients with schizophrenia meeting inclusion criteria: 1) the ICD-10 diagnostic criteria and 2) ages from 18 to 45 years. Exclusion criteria were relevant medical conditions, drug or alcohol abuse. Treatment: RIS (5 mg/day) + ARI (20 mg/day) (N=59) Comparison: RIS (5 mg/day) (N=57) Outcomes: PANSS, CGI, PRL and discontinuation rate First Author: Jin 35 Trial Design: A 6-week randomized, double-blind, placebo-controlled trial Sample: 80 in-outpatients with schizophrenia meeting inclusion criteria: 1) the CCMD-3 diagnostic criteria and 2) both sexes. Exclusion criteria were relevant medical conditions, pregnancy or breastfeeding in females. Treatment: CPZ (258 mg/day) + ARI (5 mg/day) (N=40) Comparisons: CPZ (238 mg/day) (N=40) Outcomes: BPRS, TESS, PRL and discontinuation rate First Author: Lai 37 Illness Stage: Acute patients Trial Design: An 8-week randomized, open-label trial Sample: 40 inpatients with schizophrenia meeting inclusion criteria: 1) the CCMD-3 diagnostic criteria, 2) both sexes, and 3) ages years. Exclusion criteria were relevant medical conditions, pregnancy or breastfeeding in females. Treatment: OLA (12 mg/day) +ARI (16 mg/day) (N=20) Comparison: OLA (25 mg/day) (N=10), ARI (28 mg/day) (N=10) Outcomes: PANSS, BMI, FG, TGs, TC, HDL, LDL and discontinuation rate First Author: Li 39 Trial Design: A 4-week randomized, open-label trial 19

20 Sample: All 110 patients with schizophrenia meeting inclusion criteria: 1) the ICD-10 diagnostic criteria, 2) both sexes and 3) PANSS 60. Exclusion criteria were relevant medical conditions, drug or alcohol abuse, pregnancy or breastfeeding in females. Treatment: RIS (NR) + ARI (NR) (N=55) Comparison: RIS (NR) (N=55) Outcomes: PRL, PANSS, TESS and discontinuation rate First Author: Li 40 Illness Stage: Acute patients Trial Design: An 8-week randomized, open-label trial Sample: All 80 inpatients with schizophrenia meeting inclusion criteria: 1) the CCMD-3 diagnostic criteria, 2) both sexes, 3) PANSS 60, and 4) ages from 18 to 65 years. Exclusion criteria were relevant medical conditions, drug or alcohol abuse, pregnancy or breastfeeding in females. Treatment: SUL (NR) + ARI (NR) (N=40) Comparison: SUL (NR) (N=40) Outcomes: PANSS, TESS and discontinuation rate First Author: Li 41 Trial Design: A 6-week randomized, open-label trial Sample: 70 in/outpatients with schizophrenia meeting inclusion criteria: 1) the ICD-10 diagnostic criteria, 2) both sexes, 3) PANSS 60, and 4) ages years. Exclusion criteria were relevant medical conditions, pregnancy or breastfeeding in females, allergic constitution or disease. Treatment: OLA (17 mg/day) + ARI (10 mg/day) (N=35) Comparison: OLA (17mg/day) (N=35) Outcomes: PANSS, TESS and discontinuation rate First Author: Li 42 Trial Design: A 4-week randomized, open-label trial Sample: All 60 inpatients with schizophrenia meeting inclusion criteria: 1) the CCMD-3 diagnostic criteria, 2) both sexes and 3) PANSS 60. Exclusion criteria were relevant medical conditions, drug abuse, pregnancy or breastfeeding in females. Treatment: OLA (4 mg/day) + ARI (20 mg/day) (N=32) Comparisons: OLA (4 mg/day) (N=27) Outcomes: PANSS, TESS and discontinuation rate First Author: Liang 43 20

21 Trial Design: A 4-week randomized, double-blind, placebo-controlled trial Sample: All 41 in/outpatients with schizophrenia meeting inclusion criteria: 1) the DSM-IV diagnostic criteria, 2) both sexes and 3) ages years. Exclusion criteria were relevant medical conditions, pregnancy or breastfeeding in females. Treatment: PAL (6mg/day) + ARI (10mg/day) N=20 Comparison: PAL (10 mg/day) N=21 Outcomes: PANSS, PRL and discontinuation rate First Author: Liu 44 Trial Design: A 6-week randomized, open-label trial Sample: All 70 in-outpatients with schizophrenia meeting inclusion criteria: 1) the ICD-10 diagnostic criteria, 2) both sexes and 3) PANSS >60. Exclusion criteria were relevant medical conditions, pregnancy or breastfeeding in females, allergic history or disease. Treatment: RIS (5 mg/day) + ARI (10 mg/day) (N=35) Comparison: RIS (5 mg/day) (N=35) Outcomes: PANSS, TESS and discontinuation rate First Author: Ou 45 Trial Design: An 8-week randomized, open-label trial Sample: All 70 inpatients with schizophrenia meeting inclusion criteria: 1) the CCMD-3 diagnostic criteria and 2) both sexes. Exclusion criteria were relevant medical conditions, pregnancy or breastfeeding in females. Treatment: OLA (18 mg/day) + ARI(10 mg/day) (N=35) Comparison:OLA (18 mg/day) (N=35) Outcomes: IGF-1, BMI, TC, TGs and discontinuation rate First Author: Pan 46 Trial Design: A 6-week randomized, rater masked trial Sample: All 58 patients with schizophrenia meeting inclusion criteria: 1) the CCMD-3 diagnostic criteria, 2) both sexes and 3) PRL>60 ng/ml. Exclusion criteria were relevant medical conditions, pregnancy or breastfeeding in females. Treatment: APs (NR) + ARI (10 mg/day) (N=29) Comparison: APs (NR) (N=29) Outcomes: BMI, PRL, TESS and discontinuation rate First Author: Pan 47 21

22 Illness Stage: Acute patients Trial Design: A 6-week randomized, open-label trial Sample: All 80 inpatients with schizophrenia meeting inclusion criteria: 1) the CCMD-3 diagnostic criteria, 2) both sexes, 3) PANSS 60, and 4) ages years. Exclusion criteria were relevant medical conditions, pregnancy or breastfeeding in females. Treatment: OLA (40 mg/day) + ARI (10 mg/day) (N=40) Comparison: OLA (17 mg/day) (N=29) Outcomes: PANSS. BMI, FG, INS, HOMA-IR and discontinuation rate First Author: Ren 48 Illness Stage: Acute patients Trial Design: An 8-week randomized, rater-masked trial Sample: All 72 outpatients with schizophrenia meeting inclusion criteria: 1) the ICD-10 diagnostic criteria and 2) both sexes. Exclusion criteria were relevant medical conditions. Treatment: SUL (NR) + ARI (NR) (N=36) Comparisons: SUL (NR) (N=36) Outcomes: BPRS, PRL and TESS First Author: Shu 50 Illness Stage: Acute patients Trial Design: A 12-week randomized, open-label trial Sample: All 60 female outpatients with schizophrenia meeting the CCMD-3 diagnostic criteria. Exclusion criteria were relevant medical conditions, drug or alcohol abuse. Treatment: RIS (4 mg/day) + ARI (7 mg/day) (N=30) Comparison: RIS (4 mg/day) (N=30) Outcomes: PANSS, TESS and discontinuation rate First Author: Sun 51 Trial Design: A 12-week randomized, open-label trial Sample: All 56 female inpatients with schizophrenia meeting inclusion criteria: 1) the ICD-10 diagnostic criteria and 2) ages years. Exclusion criteria were relevant medical conditions, drug or alcohol abuse. Treatment: OLA (15 mg/day) + ARI (10 mg/day) (N=28) Comparison: OLA (15 mg/day) (N=28) Outcomes: PANSS, BW, BMI, WC, PRL and TESS 22

23 First Author: Sun 52 Trial Design: A 6-week randomized, open-label trial Sample: 34 female inpatients with schizophrenia meeting inclusion criteria: 1) the CCMD-3 diagnostic criteria, 2) BPRS >25, 3) PRL >60 ng/ml and 4) ages from years. Exclusion criteria were relevant medical conditions, drug or alcohol abuse. Treatment:RIS (3 mg/day) + ARI (5 mg/day) (N=17) Comparison: RIS (4 mg/day) (N=17) Outcomes: BPRS, PRL and TESS First Author: Wang 53 Trial Design: An 8-week randomized, open-label trial Sample: All 70 female inpatients with schizophrenia meeting inclusion criteria: 1) the CCMD-3 diagnostic criteria, 2) PANSS 60, 3) no serious suicide attempts, and 4) ages years. Exclusion criteria were relevant medical conditions, pregnancy or breastfeeding in females. Treatment: RIS (5 mg/day) + ARI (5 mg/day) (N=35) Comparison: RIS (5 mg/day) (N=35) Outcomes: PANSS, TESS and discontinuation rate First Author: Wang 54 Trial Design: A 12-week randomized, open-label trial Sample: 80 inpatients with schizophrenia meeting inclusion criteria: 1) the ICD-10 diagnostic criteria, 2) both sexes, 3) PANSS 60, and 4) ages years. Exclusion criteria were relevant medical conditions, drug or alcohol abuse, pregnancy or breastfeeding in females, allergic reactions to AMI or ARI Treatment: AMI (NR) + ARI (NR) (N=40) Comparison: AMI (NR) (N=40) Outcomes: PANSS, PRL, TESS and discontinuation rate First Author: Xiong 55 Trial Design: An 8-week randomized, open-label trial Sample: All 68 patients with schizophrenia meeting inclusion criteria: 1) the CCMD-3 diagnostic criteria, 2) both sexes and 3) PANSS 60. Treatment: RIS (4 mg/day) +ARI (10 mg/day) (N=34) Comparison: RIS (4 mg/day) (N=34) 23

24 Outcomes: PANSS, TESS and discontinuation rate First Author: Xu 56 Trial Design: A 6-week randomized, open-label trial Sample: All 68 in-outpatients with schizophrenia meeting inclusion criteria: 1) the ICD-10 diagnostic criteria, 2) both sexes, 3) PANSS 60, and 4) ages years. Exclusion criteria were relevant medical conditions, drug or alcohol abuse, pregnancy or breastfeeding in females, and diagnosis of refractory schizophrenia. Treatment: QUE (604 mg/day) + ARI (10 mg/day) (N=31) Comparisons: QUE (624 mg/day) (N=32) Outcomes: PANSS, BW, WC, BMI, PRL and discontinuation rate First Author: Xue 57 Trial Design: A 6-week randomized, rater-masked trial Sample: All 68 male inpatients with schizophrenia meeting inclusion criteria: 1) the CCMD-3 diagnostic criteria, 2) PRL >26.26 ng/ml and 3) BPRS >25. Exclusion criteria were relevant medical conditions and other drugs associated with PRL increases. Treatment: RIS (5 mg/day) + ARI (5 mg/day) (N=34) Comparison: RIS (5 mg/day) (N=34) Outcomes: BPRS, PRL and TESS. First Author: Yang 58 Illness Stage: Acute patients Trial Design: An 8-week randomized, double-blind, placebo-controlled trial Sample: All 180 patients with schizophrenia meeting inclusion criteria: 1) both the CCMD-3 and ICD-10 diagnostic criteria, 2) both sexes, 3) PANSS 60, and 4) ages from 19 to 62 years. Exclusion criteria were relevant medical conditions, drug or alcohol abuse. Treatment: RIS (5 mg/day) + ARI (10 mg/day) N=60 Comparison: RIS (5 mg/day) N=6, ARI (5 mg/day) N=60 Outcomes: PANSS, TESS and discontinuation rate First Author: Yang 59 Trial Design: An 8-week randomized, open-label trial Sample: All 212 in/outpatients with schizophrenia meeting inclusion criteria: 1) the CCMD-3 diagnostic criteria, 2) both sexes, 3) PANSS 60 and 4) ages years. Exclusion criteria were relevant medical conditions, drug or alcohol abuse, pregnancy or breastfeeding in females, or 24

25 treatment-failure with RIS. Treatment: RIS (NR) + ARI (NR) (N=105) Comparison: RIS (NR) (N=107) Outcomes: PANSS and TESS and discontinuation rate First Author: Zhao 61 Trial Design: A 12-week randomized, open-label trial Sample: All 56 female in-outpatients with schizophrenia meeting inclusion criteria: 1) the CCMD-3 diagnostic criteria, 2) PANSS<60, 3) ages years, and 4) treatment with RIS (3-8 mg/d) for 4 weeks with weight gain >4kg. Exclusion criteria were relevant medical conditions. Treatment: RIS (NR) + ARI (10 mg/day) (N=28) Comparison: RIS (NR) (N=28) Outcomes: PANSS, BW, BMI, WC, PRL and TESS. First Author: Zhou 62 Trial Design: A 24-week randomized, rater-masked trial Sample: All 60 in/outpatients with schizophrenia meeting inclusion criteria: 1) the ICD-10 diagnostic criteria, 2) both sexes, 3) ages years, and 4) who were in treatment with RIS with a maintenance dose. Exclusion criteria were relevant medical conditions, drug or alcohol abuse. Treatment: RIS (4 mg/day) + ARI (10 mg/day) (N=30) Comparison: RIS (4 mg/day) (N=30) Outcomes: BW, BMI, WC, TESS and discontinuation rate First Author: Zhou 63 Trial Design: A 24-week randomized, open-label trial Sample: All 100 female in-outpatients with schizophrenia meeting inclusion criteria: 1) the CCMD-3 diagnostic criteria, 2) PRL <20 ng/ml, 3) PANSS 60, and 4) ages years. Exclusion criteria were relevant medical conditions, drug or alcohol abuse, amenorrhea, pregnancy or breastfeeding in females. Treatment: RIS (NR) + ARI (5 mg/day) (N=50) Comparison: RIS (NR) (N=50) Outcomes: PANSS, CGI, TESS and PRL. First Author: Zhuo 64 25

26 Trial Design: A 12-week randomized, double-blind, placebo-controlled trial Sample: All 60 female patients with schizophrenia meeting inclusion criteria: 1) who met the diagnostic criteria (not reported), 2) PRL>30 ng/ml, 3) AP-induced amenorrhea or galactorrhea, and 4) treatment with SUL ( mg/d) or RIS (2-6 mg/d) or OLA (5-20 mg/d) for >6 months. Exclusion criteria were relevant medical conditions, other drugs associated with PRL increases. Treatment: APs (NR) + ARI (23 mg/day) (N=30) Comparison: APs (NR) (N=30) Outcomes: BMI, PRL, TESS and discontinuation rate ADR, adverse drug reaction; AMI, amisulpiride; AP, antipsychotic; ARI, aripiprazole; BMI, body mass index; BW, body weight; BPRS, Brief Psychiatric Rating Scale; CCMD-3, China's Mental Disorder Classification and Diagnosis, standard 3rd edition; CGI, Clinical Global Impressions scale; CLO, clozapine; CPT, Career Personality Test; CPZ, chlorpromazine; CPZE, chlorpromazine equivalents; DSM-IV, Diagnostic and Statistical Manual of Mental Disorders, 4th edition; FG, fasting glucose; GAF, Global Assessment of Functioning; HAL, haloperidol; HDL-C, high density lipoprotein cholesterol; HOMA-IR, homeostasis model assessment insulin resistance index; IGF-1, insulin like growth factor-1; INS, insulin; ICD-10, International Classification of Diseases, 10th edition; LDL-C, low density lipoprotein cholesterol; NR, not reported; OLA, olanzapine; PAL, paliperidone; PANSS, Positive and Negative Syndrome Scale; PRL, prolactin; QUE, quetiapine; RCT, randomized clinical trial; RIS, risperidone; SUL, sulpiride; TESS, treatment emergent symptom scale; TC, total cholesterol; TGs, triglycerides; WBC, White Blood Cell count; WC, waist circumference; WCST, Wisconsin Card Sorting Test. a RCTs are in order by reference number. 26

27 SUPPLEMENTARY FIGURE S1. Computerized database search PubMed, PsycINFO, Embase, Cochrane Library databases, the Cochrane Controlled Trials Register and Chinese databases (WanFang Database, Chinese Biomedical database and China Journal Net) were searched. 27

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